N-aryl thienyl-, furyl-, and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin

Abstract

Thienyl-, furyl- and pyrrolyl-sulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

We claim:  
     
       1. A compound that has formula I:                    
       or a pharmaceutically acceptable salt, acid or ester thereof, wherein: 
       Ar 1  is a five or six membered aromatic ring;  
       Ar 2  has formula IV:                    
        in which  
       X is S, O or NR 11  in which R 11  is hydrogen or has up to about 30 carbon atoms, and is selected from alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 15  and S(O) n R 15  in which n is 0-2; R 15  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R 11  and R 15  are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R 16 , CO 2 R 16 , SH, S(O) n R 16  in which n is 0-2, NHOH, NR 12 R 16 , NO 2 , N 3 , OR 16 , R 12 NCOR 16  or CONR 12 R 16 ; R 16  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R 12 , which is selected independently from R 11  and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 17  and S(O) n R 17  in which n is 0-2; and R 17  is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R 11 , R 12 , R 15  and R 16  is unsubstituted or substituted with any of the groups set forth for Z; and  
       R 8 , R 9  and R 10  are each independently selected as follows from (i) or (ii):  
       (i) R 8 , R 9  and R 10 , which each are hydrogen or have up to about 50 carbon atoms, and are each independently selected from halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R 18 , acetoxy-(CH═CH)—, CO 2 R 18 , SH, (CH 2 ) r C(O)(CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r C(O)(CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s C(O)(CH 2 ) n R 18 , (CH 2 ) r NH(CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s NH(CH 2 ) n R 18 , (CH 2 ) r C(O)NH(CH 2 ) n R 18 , C(O)(CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r R 18 , S(O) m R 18  in which m is 0-2, s, n and r are each independently 0 to 6, HNOH, NR 18 R 19 , NO 2 , N 3 , OR 18 , R 19 NCOR 18  and CONR 19 R 18 , in which R 19  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 20  and S(O) n R 20  in which n is 0-2; and R 18  and R 20  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and any of the groups set forth for R 8 , R 9  and R 10  are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R 21 , CO 2 R 21 , SH, S(O) n R 21  in which n is 0-2, NHOH, NR 22 R 21 , NO 2 , N 3 , OR 21 , R 22 NCOR 21  or CONR 22 R 21 ; R 22  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 23  and S(O) n R 23  in which n is 0-2; and R 21  and R 23  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl, with the proviso that if R 8  is NR 18 R 19 , OR 18 , R 19 NCOR 18 , CONR 19 R 18 , CO 2 R 18 , (CH 2 ) r NH(CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s NH(CH 2 ) n R 18 , (CH 2 ) r C(O)NH(CH 2 ) n R 18 , C(O)(CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r NH(CH 2 ) n R 18  or (CH 2 ) r R 18  and R 18  is an aryl group having 5 or 6 members, then the aryl group has at least two substituents, or  
       (ii) any two of R 8 , R 9  and R 10  with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, having from about 3 to about 16 members, that is substituted with one or more substituents, each substituent is independently selected from Z; the other of R 8 , R 9  and R 10  is selected as in (i); and the heteroatoms are NR 11 , O, or S, with the proviso that Ar 2  is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl or 5-halo-3-loweralkylbenzo[b]pyrrolyl.  
     
     
       2. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof, wherein R 1  is halide, methyl or (C 9 -C 13 ) alkyl. 
     
     
       3. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein Ar 1  is a phenyl group. 
     
     
       4. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein R 1  is H, lower alkyl, halide or pseudohalide; and R 2  is lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl or hydrogen. 
     
     
       5. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof, wherein R 1  is selected from halide, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7  and cyclo-C 3 H 7 , and R 2  is selected from H, CH 3 , C 2 H 5 , CF 3 , C 2 F 5 , n-C 3 H 7  and cyclo-C 3 H 7 . 
     
     
       6. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof in which Ar 2  formula IVA or IVB:                    
       wherein: 
       X is NR 11 , O, or S;  
       R 8  is selected from among (CH 2 ) r C(O)(CH 2 ) n R 18 , (CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r C(O)(CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s C(O)(CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s NH(CH 2 ) n R 18 , C═N(OH)(CH 2 ) r R 18 , (CH 2 ) r C(O)NH(CH 2 ) n R 18 , C(O)(CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r NH(CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r C(O)NH(CH 2 ) n R 18 , (CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r R 18 , with the proviso that if R 8  is (CH 2 ) r C(O)NH(CH 2 ) n R 18 , (CH 2 ) r C(O)NH(CH 2 ) n R 18  or (CH 2 ) r R 18 , and R 18  is phenyl, the phenyl group is substituted at least two positions;  
       and R 9  and R 10  are independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R 18 , (OAC)CH═CHR 18 , CO 2 R 18 , SH, (CH 2 ) r C(O)(CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r C(O)(CH═CH) s (CH 2 ) n R 18 , (CH 2 ) r (CH═CH) s C(O)(CH 2 ) n R 18 , (CH 2 ) r NH(CH═CH) s (CH 2 ) n R 18 , C═N(OH)(CH 2 ) r R 18 , (CH 2 ) r (CH═CH) s NH(CH 2 ) n R 18 , (CH 2 ) r C(O)NH(CH 2 ) n R 18 , C(O)(CH 2 ) r NH(CH 2 ) n R  18 , (CH 2 ) r NH(CH 2 ) n R 18 , (CH 2 ) r R 18 , S(O) m R 18  in which m is 0-2, s, n and r are each independently 0 to 6, HNOH, NR 18 R 19,  NO 2 , N 3 , OR 18 , R 19 NCOR 18  and CONR 19 R 18 , in which R 19  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 20  and S(O) n R 20  in which n is 0-2; and R 18  and R 20  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl.  
     
     
       7. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein R 18  is aryl or heteroaryl. 
     
     
       8. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein R 18  is phenyl or pyrimidinyl. 
     
     
       9. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof wherein R 9  and R 10  are hydrogen, halide, loweralkyl, or halo loweralkyl. 
     
     
       10. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein R 19  is hydrogen or lower alkyl; and R 18  is aryl. 
     
     
       11. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein Ar 2  is phenylaminocarbonylthienyl, phenylaminocarbonylfuryl, phenylaminocarbonylpyrrolyl, phenylacetylthienyl, phenylacetylfuryl, phenylacetylpyrrolyl, acetoxystyrylthienyl, acetoxystyrylfuryl or acetoxystyrylpyrrolyl, with the proviso that, when Ar 2  is a phenylaminocarbonylthienyl, phenylaminocarbonylfuryl, phenylaminocarbonylpyrrolyl, the phenyl group is substituted with at least two substituents selected from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R 21  , CO 2 R 21  , SH, S(O) n R 21  in which n is 0-2, NHOH, NR 22 R 21 , NO 2 , N 3 , OR 21 , R 22 NCOR 21  or CONR 22 R 21 ; R 22  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R 23  and S(O) n R 23  in which n is 0-2; and R 21  and R 23  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl. 
     
     
       12. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein X is S, O, NR 11  in which R 11  is hydrogen, or loweralkyl, or aryl, which is unsubstituted or substituted with loweralkyl, halogen, hydrogen or loweralkyl. 
     
     
       13. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein R 11  is phenyl. 
     
     
       14. A compound of  claim 1  or pharmaceutically acceptable salts, acids or esters thereof, wherein Ar 2  has formula VI:                    
       wherein: 
       M is (CH 2 ) m C(O)(CH 2 ) r , (CH 2 ) m C(O)NH(CH 2 ) r , CH(OH)(CH 2 ) r , (CH 2 ) m (CH═CH)(CH 2 ) r , (CH 2 ) m C(O)(CH 2 ) s NH(CH 2 ) r , (CH 2 ) m (CH═CH)(CH 2 ) r , C═N(OH)(CH 2 ) r , (CH 2 ) m C(O)(CH═CH) s NH(CH 2 ) r , CH(CH 3 )C(O)(CH 2 ) r , CH(CH 3 )C(O)(CH 2 ) m (CH═CH)(CH 2 ) r , (CH 2 ) r , (CH 2 ) r O or C(O)O, in which m,s and r are each independently 0 to 6;  
       R 31 , R 32 , R 33 , R 34  and R 35  are each independently selected from (i) or (ii) as follows:  
       (i) R 31 , R 32 , R 33 , R 34  and R 35  are each independently selected from among H, OH, NHR 38 , CONR 38 R 39 , NO 2 , cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkylaminocarbonyl)alkyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy and formyl; or  
       (ii) at least two of R 31 , R 32 , R 33 , R 34  and R 35 , which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R 31 , R 32 , R 33 , R 34  and R 35  are selected as in (i); and  
       R 38  and R 39  are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, with the proviso that when M is (CH 2 ) m C(O)NH(CH 2 ) r , then at least two of R 31 , R 32 , R 33 , R 34  and R 35  are not hydrogen.  
     
     
       15. A compound of  claim 14 , wherein M is (CH 2 ) m C(O)(CH 2 ) r , (CH 2 ) m C(O)NH(CH 2 ) r , (CH 2 ) m (CH═CH)(CH 2 ) r , (CH 2 ) m C(O)(CH 2 ) s NH(CH 2 ) r , (CH 2 ) m (CH═CH)(CH 2 ) r , C═N(OH)(CH 2 ) r , CH(OH)(CH 2 ) r , (CH 2 ) r , (CH 2 ) r O or C(O)O. 
     
     
       16. A compound of  claim 14  or a pharmaceutically acceptable salt, acid or ester thereof, wherein R 31 , R 32 , R 33 , R 34  and R 35  are selected from (i) or (ii) 
       (i) R 31 , R 32 , R 33 , R 34  and R 35  are each independently selected from among lowealkyl, halide, haloloweralkyl, and loweralkoxy; and  
       (ii) at least two of R 31 , R 32 , R 33 , R 34  and R 35  form ethylenedioxy or methylenedioxy and the others are selected as in (i).  
     
     
       17. A compound of  claim 14  or pharmaceutically acceptable salts, acids or esters thereof, wherein M is                    
       in which R 40  is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl. 
     
     
       18. A compound of  claim 14  or pharmaceutically acceptable salts, acids or esters thereof, wherein at least two of R 31 , R 32 , R 33 , R 34  and R 35 , which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl. 
     
     
       19. A compound of  claim 14  or pharmaceutically acceptable salts, acids or esters thereof, wherein at least one of R 31  and R 35  is other than hydrogen. 
     
     
       20. A compound of  claim 14  or pharmaceutically acceptable salts, acids or esters thereof, wherein Ar 2  has formula VII:                    
       in which W is CH 2  or NH. 
     
     
       21. A compound of  claim 14  or a pharmaceutically acceptable salt, acid or ester thereof, wherein M is selected from                    
     
     
       22. A compound of  claim 17 , wherein R 40  is methyl, ethyl or hydrogen. 
     
     
       23. A compound of  claim 14  or a pharmaceutically acceptable salt, acid or ester thereof, wherein R 31 , R 32 , R 33 , R 34  and R 35  are selected from (i) or (ii): 
       (i) R 31 , R 32 , R 33 , R 34  and R 35  are each independently selected from loweralkyl, haloloweralkyl, phenyl, alkoxy, loweralkylsulfonylaminoloweralkyl, cyanoloweralkyl, acetyl, loweralkoxycarbonyl, cyano, OH, acetoxyloweralkyl, hydroxy loweralkyl, acetoxy loweralkoxy or loweralkoxycarbonyl; or  
       (ii) R 32  and R 33  or R 33  and R 34  form alkylene dioxy, and the others of R 31 , R 32 , R 33 , R 34  and R 35  are selected as in (i) .  
     
     
       24. A compound of  claim 14  or a pharmaceutically acceptable salt, acid or ester thereof, wherein R 31 , R 33  and R 35  are selected from (i) or (ii): 
       (i) R 33  and R 35  are other than hydrogen and are selected from loweralkyl or lower alkoxy, or  
       (ii) at least one of R 31  or R 35  is loweralkyl or lower alkoxy, and R 32  and R 33  or R 33  and R 34  form methylenedioxy or ethylenedioxy.  
     
     
       25. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof, wherein R 9  and R 10  form a ring so that Ar 2  is benzo[b]thienyl, benzo[b]furyl, or indolyl, with the proviso that there is one or more substituent and they are other than 5-halo and 3-loweralkyl, and the other of R 8 , R 9  and R 10  is selected from aryl, (CH 2 ) r R 18 , C(O)R 18 , CO 2 R 18 , NR 18 R 19 , SH, S(O) n R 18  in which n is 0-2, HNOH, NO 2 , N 3 , OR 18 , R 19 NCOR 18  and CONR 19 R 18 . 
     
     
       26. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof, wherein R 1  is halide or CH 3 , and R 2  is H, CH 3 , C 2 H 5 , or CF 3 . 
     
     
       27. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof, wherein Ar 2  is thienyl. 
     
     
       28. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof, wherein Ar 2  is furyl. 
     
     
       29. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof, wherein Ar 2  is pyrrolyl. 
     
     
       30. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof that is a (phenylacetyl)thiophenesulfonamide. 
     
     
       31. A compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof that is a (phenyoxy)thiophenesulfonamide. 
     
     
       32. A pharmaceutical composition, comprising a compound of  claim 1  or a pharmaceutically acceptable salt, acid, or ester thereof in a pharmaceutically acceptable carrier. 
     
     
       33. A method for the treatment of endothelin-mediated diseases, comprising administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, ester or acid thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease. 
     
     
       34. The method of  claim 33 , wherein the disease is selected from the group consisting of hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, wounds, gastroenteric disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock and hemorrhagic shock. 
     
     
       35. The method of  claim 33 , wherein the disease is selected from the group consisting of hypertension, cardiovascular disease, pulmonary hypertension, erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock and hemorrhagic shock. 
     
     
       36. The method of  claim 33 , wherein the disease is selected from the group consisting of asthma and inflammatory diseases. 
     
     
       37. A method for inhibiting the binding of an endothelin peptide to endothelin A  (ET A ) or endothelin B  (ET B ) receptors, comprising contacting the receptors an endothelin peptide and with a compound of  claim 1  or a pharmaceutically acceptable salt, ester or acid thereof, wherein: 
       the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.  
     
     
       38. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with a compound of  claim 1  or a pharmaceutically acceptable salt, ester or acid thereof. 
     
     
       39. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, ester or acid thereof, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease. 
     
     
       40. An article of manufacture, comprising packaging material and a compound of  claim 1  or a pharmaceutically acceptable salt, ester or acid thereof within the packaging material, wherein the compound is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC 50  of less than about 10 μM, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder. 
     
     
       41. A compound or a pharmaceutically acceptable salt, acid or ester of a compound of  claim 15 , wherein R 31 , R 32 , R 33 , R 34  and R 35  are selected from (i) or (ii) 
       (i) R 31 , R 32 , R 33 , R 34  and R 35  are each independently selected from among loweralkyl, halide, haloloweralkyl, and loweraloxy; and  
       (ii) at least two of R 31 , R 32 , R 33 , R 34 and R 35  form ethylenedioxy or methylenedioxy and the others are selected as in (i).  
     
     
       42. A compound or a pharmaceutically acceptable salt, acid or ester of a compound  claim 41 , wherein M is                    
       in which R 40  is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl. 
     
     
       43. A compound or a pharmaceutically acceptable salt, acid or ester of a compound  claim 42 , wherein at least two of R 31 , R 32 , R 33 , R 34  and R 35 , which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl. 
     
     
       44. A compound or a pharmaceutically acceptable salt, acid or ester of a compound  claim 42 , wherein at least one of R 31  and R 35  is other than hydrogen. 
     
     
       45. A compound or a pharmaceutically acceptable salt, acid or ester of a compound  claim 44 , wherein Ar 2  has formula VII:                    
       in which W is CH 2  or NH. 
     
     
       46. A compound of  claim 42  or a pharmaceutically acceptable salt, acid or ester thereof, wherein M is selected from                    
     
     
       47. A compound of  claim 42  or a pharmaceutically acceptable salt, acid or ester thereof, wherein R 40  is methyl, ethyl or hydrogen. 
     
     
       48. A compound of  claim 47  or a pharmaceutically acceptable salt, acid or ester thereof, wherein R 31 , R 33 , and R 35  are selected from (i) or (ii): 
       (i) R 33  and R 35  are other than hydrogen and are selected from loweralkyl or lower alkoxy, or  
       (ii) at least one of R 31  or R 35  is loweralkyl or lower alkoxy, and R 32  and R 33  or R 33  and R 34  form methylenedioxy or ethylenedioxy.  
     
     
       49. A compound of  claim 48  or a pharmaceutically acceptable salt, acid or ester thereof, wherein R 9  and R 10  form a ring so that Ar 2  is benzo[b]thienyl, benzo[b]furyl, or indolyl, with the proviso that there is one or more substituent and they are other than 5-halo and 3-loweralkyl, and the other of R 8 , R 9  and R 10  is selected from aryl, (CH 2 ) r R 18 , C(O)R 18 , CO 2 R 18 , NR 18 R 19 , SH, S(O) n R 18  in which n is 0-2, HNOH, NO 2 , N 3 , OR 18 , R 19 NCOR 18  and CONR 19 R 18 . 
     
     
       50. A compound of  claim 48  or a pharmaceutically acceptable salt, acid or ester thereof, wherein Ar 2  is thienyl. 
     
     
       51. A compound of  claim 41  or a pharmaceutically acceptable salt, acid or ester thereof, wherein Ar 2  is thienyl. 
     
     
       52. The method of  claim 33 , wherein the disease is glaucoma.